Background and objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability. Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. Results: A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3). Discussion: The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability.

Rossi, S., Rubegni, A., Riso, V., Barghigiani, M., Bassi, M. T., Battini, R., Bertini, E., Cereda, C., Cioffi, E., Criscuolo, C., Dal Fabbro, B., Dato, C., D'Angelo, M. G., Di Muzio, A., Diamanti, L., Dotti, M. T., Filla, A., Gioiosa, V., Liguori, R., Martinuzzi, A., Massa, R., Mignarri, A., Moroni, R., Musumeci, O., Nicita, F., Orologio, I., Orsi, L., Pegoraro, E., Petrucci, A., Plumari, M., Ricca, I., Rizzo, G., Romano, S., Rumore, R., Sampaolo, S., Scarlato, M., Seri, M., Stefan, C., Straccia, G., Tessa, A., Travaglini, L., Trovato, R., Ulgheri, L., Vazza, G., Orlacchio, A., Silvestri, G., Santorelli, F. M., Melone, M. A. B., Casali, C., Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network, <<NEUROLOGY. GENETICS>>, 2022; 8 (2): e664-N/A. [doi:10.1212/NXG.0000000000000664] [http://hdl.handle.net/10807/200288]

Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network

Rossi, Salvatore;Bertini, Enrico;Silvestri, Gabriella
;
2022

Abstract

Background and objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability. Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. Results: A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3). Discussion: The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability.
2022
Inglese
Rossi, S., Rubegni, A., Riso, V., Barghigiani, M., Bassi, M. T., Battini, R., Bertini, E., Cereda, C., Cioffi, E., Criscuolo, C., Dal Fabbro, B., Dato, C., D'Angelo, M. G., Di Muzio, A., Diamanti, L., Dotti, M. T., Filla, A., Gioiosa, V., Liguori, R., Martinuzzi, A., Massa, R., Mignarri, A., Moroni, R., Musumeci, O., Nicita, F., Orologio, I., Orsi, L., Pegoraro, E., Petrucci, A., Plumari, M., Ricca, I., Rizzo, G., Romano, S., Rumore, R., Sampaolo, S., Scarlato, M., Seri, M., Stefan, C., Straccia, G., Tessa, A., Travaglini, L., Trovato, R., Ulgheri, L., Vazza, G., Orlacchio, A., Silvestri, G., Santorelli, F. M., Melone, M. A. B., Casali, C., Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network, <<NEUROLOGY. GENETICS>>, 2022; 8 (2): e664-N/A. [doi:10.1212/NXG.0000000000000664] [http://hdl.handle.net/10807/200288]
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